Thromboembolism in a patient with transient eosinophilia

We report here a case of thromboembolism occurring in a 29-year-old woman with transient eosinophilia. Eosinophilia for at least 11 days was followed by pulmonary embolism. Both reperfusion of pulmonary arteries and disappearance of deep vein thrombi were obtained by treatment with urokinase, tissue plasminogen activator, and heparin. Although the causes of eosinophilia were not specified, we suggested a causative correlation of elevated serum levels of eosinophil granule proteins with the development of thromboembolism.     

Grade of eosinophilia versus symptoms in patients with dysphagia and esophageal eosinophilia

The aim of this study was to assess whether the symptom severity and health‐related quality of life (HRQL) of patients with dysphagia and esophageal eosinophilia correlate with disease activity as expressed by the number of eosinophils in the esophageal mucosa. This study included newly diagnosed (n = 58) or relapsed patients (n = 7), where 40% were diagnosed in connection with esophageal bolus impaction. The mean age was 45 years (19–88), and 74% were men. Symptoms and HRQL were recorded using the Watson Dysphagia Scale (WDS), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Oesophageal Module 18 and the Short Form‐36 Questionnaire. Histological samples gathered from the proximal and distal esophageal mucosa were stained using both hematoxylin and eosin (HE) and an immunohistochemical (IHC) technique against ‘Eosinophil Major Basic Protein,’ and the peak number of eosinophils per high‐power field was assessed. More eosinophils were detected after IHC staining than HE staining (P < 0.001). No correlation was found between symptoms or the HRQL and the number of eosinophils. However, higher numbers of eosinophils at the proximal esophagus were found in patients with concomitant bolus impaction (IHC P < 0.05 and HE P < 0.05) and could serve as a risk marker.     

Major basic protein binding to thrombomodulin potentially contributes to the thrombosis in patients with eosinophilia

Summary. The contribution of an eosinophil granule protein, major basic protein (MBP), to the pathogenesis of thrombosis seen in patients with eosinophilia was investigated. The sera from eosinophilic patients containing elevated levels of MBP inhibited thrombomodulin (TM) function as a cofactor for the thrombin-catalysed activation of protein C more significantly than those from normal individuals (means 48.5% v 17.4%, respectively). It was suggested that the binding of mature MBP in the sera to TM was electrostatic, because mature MBP (pi 10.9) bound to TM, whereas pro-MBP (pi 6.2) did not. The inhibition of TM cofactor activity by eosinophil granule proteins was mainly attributed to the mature MBP, because MBP-depleted eosinophil granule proteins did not inhibit TM cofactor activity significantly. This inhibition seemed to be due to the specific thrombin-binding to TM being blocked. We concluded that eosinophil granule proteins, particularly MBP, potentially contribute to the hypercoagulation seen in some conditions of eosinophilia, at least because of the inhibition of TM function as a cofactor of the anticoagulation system.     

肝细胞癌癌组织和癌旁肝组织Ep-CAM和C-Kit表达及其意义探讨*

目的 探讨肝细胞癌（HCC）患者癌组织和癌旁肝组织C-Kit蛋白和肿瘤干细胞标志上皮细胞黏附分子（EpCAM）蛋白表达的变化。方法 2014年3月~2017年1月我院经手术切除治疗的HCC患者癌组织和癌旁肝组织标本90份,采用免疫组化染色法检测癌组织和癌旁肝组织Ep-CAM蛋白和C-Kit蛋白表达情况,并比较不同分化、有无包膜、不同病灶大小、术前不同血清甲胎蛋白（AFP）水平癌组织Ep-CAM蛋白和C-Kit蛋白表达阳性率的差异。结果 在本组90例HCC患者肝组织中,癌组织Ep-CAM蛋白和C-Kit蛋白表达阳性率分别为65.6%和74.4%,均显著高于癌旁组织的11.1%和4.4%,差异具有统计学意义（P<0.05）;50例Ⅲ级和Ⅳ级组织学分化、49例术前血清AFP>400 ng/ml、28例发生血管浸润的癌组织Ep-CAM蛋白表达阳性率分别为76.0%、79.6%和82.1%,显著高于40例Ⅰ级和Ⅱ级组织学分化、41例血清AFP≤400 ng/ml和62例未发生肿瘤血管浸润的癌组织（分别为52.5%、48.8%和58.1%）;Ⅲ级和Ⅳ级组织学分化、术前血清AFP>400 ng/ml、发生血管浸润的癌组织C-Kit蛋白表达阳性率分别为86.0%、87.8%和89.3%,也显著高于Ⅰ级和Ⅱ级组织学分化、血清AFP≤400 ng/ml和未发生肿瘤血管浸润的癌组织（分别为60.0%、58.5%和67.7%）,差异均具有统计学意义（P<0.05）。结论 HCC患者癌组织Ep-CAM蛋白和C-Kit蛋白表达阳性率显著增高,并与肿瘤组织学分级、术前血清AFP水平和是否发生肿瘤血管浸润有关,其临床意义还有待进一步探讨。     

Serum levels of major basic protein in patients with or without eosinophilia: measurement by enzyme-linked immunosorbent assay

Summary. A bone marrow proteoglycan (BMPG) has been purified which consists of the same amino acid sequence as that of pro-MBP, and produced two anti-BMPG mAbs. Serum levels of major basic protein (MBP), a cationic protein rich in the eosinophil granule, were measured in patients with eosinophilia or allergic diseases by an enzyme-linked immunosorbent assay (ELISA) using these mAbs. The serum levels of MBP in patients with eosinophilia ( n = 64) and in those with allergic diseases without eosinophilia ( n = 32) were elevated significantly ( P < 0·001 and P = 0·038, respectively). There was a weak positive correlation between the serum levels of MBP and the eosinophil counts in the patients with eosinophilia ( r = 0·38). Among these patients, extremely high serum levels of MBP were found in those with hypereosinophilic syndrome (HES) and Kimura's disease. Serum levels of MBP decreased more slowly than the eosinophil counts in patients with eosinophilia when treated by glucocorticoids. We conclude that measurement of serum levels of MBP is useful in evaluating the total-body proliferation and infiltration of eosinophils more accurately than following-up the eosinophil counts alone.     

T淋巴细胞介导的小鼠免疫性肝纤维化模型的建立及形态学观察

目的 建立刀豆蛋白A诱导的T淋巴细胞介导的小鼠免疫性肝纤维化模型凌晨进行形态学观察。方法 BALB/C小鼠随机分组。模型组、CD4抗体处理组、CD8抗体处理组、地塞米松处理组和裸鼠组静脉注射刀豆蛋白A;CD4、CD8抗体处理组、地塞米松注射组和裸鼠组共注射5周,模型组共注射20周,分别于相应的时间点取血、取肝脏组织统一保存。检测ALT水平,进行肝脏组织苏木精-伊红染色、免疫组织化学染色和Van Gieson胶原纤维染色。结果 模型组接受刀豆蛋白A刺激后,ALT水平明显高于正常对照组,而CD4抗体处理组、地塞米松处理组和裸鼠组ALT水平明显低于模型组,CD8抗体处理组ALT水平则与阳性组无明显差异。肝组织冰冻切片免疫组织化学染色提示肝组织内淋巴细胞浸润以CD4^ T淋巴细胞为主。模型组病理检查提示肝纤维化发生。结论 反复刀豆蛋白A刺激可以建立T淋巴细胞介导的小鼠免疫性肝纤维化模型。     

Noninvasive methods for prediction of esophageal varices in pediatric patients with portal hypertension

AIM: To evaluate clinical and laboratory parameters for prediction of bleeding from esophageal varices (EV) in children with portal hypertension. METHODS: Retrospective study of 103 children (mean age: 10.1 ± 7.7 years), 95.1% with intrahepatic portal hypertension. All patients had no history of bleeding and underwent esophagogastroduodenoscopy for EV screening. We recorded variceal size (F1, F2 and F3), red-color signs and portal gastropathy, according to the Japanese Research Society for Portal Hypertension classification. Patients were classified into two groups: with and without EV. Seven noninvasive markers were evaluated as potential predictors of EV: (1) platelet count; (2) spleen size z score, expressed as a standard deviation score relative to normal values for age; (3)platelet count to spleen size z score ratio; (4) platelets count to spleen size (cm) ratio; (5) the clinical prediction rule (CPR); (6) the aspartate aminotransferase to platelet ratio index (APRI); and (7) the risk score. RESULTS: Seventy-one children had EV on first endoscopy. On univariate analysis, spleen size, platelets, CPR, risk score, APRI, and platelet count to spleen size z score ratio showed significant associations. The best noninvasive predictors of EV were platelet count [area under the receiver operating characteristic curve (AUROC) 0.82; 95%CI: 0.73-0.91], platelet: spleen size z score (AUROC 0.78; 95%CI: 0.67-0.88), CPR (AUROC 0.77; 95%CI: 0.64-0.89), and risk score (AUROC 0.77; 95%CI: 0.66-0.88). A logistic regression model was applied with EV as the dependent variable and corrected by albumin, bilirubin and spleen size z score. Children with a CPR < 114 were 20.7-fold more likely to have EV compared to children with CPR > 114. A risk score > -1.2 increased the likelihood of EV (odds ratio 7.47; 95%CI: 2.06-26.99). CONCLUSION: Children with portal hypertension with a CPR below 114 and a risk score greater than -1.2 are more likely to have present EV. Therefore, these two tests can be helpful in selecting childr     

增强肝纤维化试验在慢性丙肝患者肝纤维化诊断中准确性的研究

目的探讨增强肝纤维化（ELF）试验在慢性丙肝患者肝纤维化诊断中的准确性。方法选取2011年1月-2013年4月在本院进行肝活组织检查的慢性丙型肝炎患者156例,对其临床资料进行前瞻性研究。ELF试验包括3项血清标志物的检测：透明质酸（HA）、基质金属蛋白酶组织抑制物-1（TIMP-1）和Ⅲ型前胶原氨基端肽（PⅢNP）。采用Metavir评分系统将肝纤维化进行分期。结果在肝纤维化的诊断中,ELF=7.72时,诊断显著肝纤维化（F≥2）的ROC曲线下面积（AUROC）为0.94（95%CI：0.89-0.97）,敏感性为93.0%,特异性为83.0%;ELF试验诊断显著肝纤维化的敏感性和特异性分别为93.3%和81.0%。在肝硬化的诊断中,ELF=9.30时,诊断肝硬化（F=4）的AUROC为0.94（95%CI：0.88-0.96）,敏感性为93.0%,特异性为86.0%。结论 ELF试验是有效诊断慢性丙肝患者肝纤维化的无创性检查方法,能够准确的诊断肝纤维化分期和肝硬化。     

Tumor-associated eosinophilia in interleukin-2-treated patients: evidence of toxic eosinophil degranulation on bladder cancer cells

Summary Blood eosinophilia in tumor patients treated with interleukin-2 (IL-2) is well known and is regarded as evidence of toxicity or as a side-effect [Lotze et al. (1986) Arch Surg 121:1373–1379; West et al. (1987) N Engl J Med 316:898–905]. We recently described a new local IL-2 approach to therapy for advanced bladder carcinoma that allows, for the first time, high-dose continuous adminstration of natural interleukin-2 (nIL-2) at the tumor site without side-effects [Huland and Huland (1989) Cancer Res 49:5469–5474]. Tumor-associated eosinophilia of up to 65% (i.e. eosinophils constituting 65% of leukocytes) was seen in four of five patients after treatment, but never before treatment or in untreated controls. Activated eosinophils were attached to bladder tumor cells. Local activation was seen only after natural IL-2 treatment and was determined by cytological criteria and by staining with monoclonal antibody (mAb) EG1 directed against all eosinophil granule proteins and mAb EG2 directed against the active secretory granule proteins of the eosinophils. Bladder cancer cells in urinary sediment also stained with these two mAbs, revealing active degranulation of eosinophils on bladder tumor cells. The number of eosinophils in blood increased, however, without signs of activation. These data constitute strong evidence that activated eosinophils in vivo are involved in the IL-2-induced antitumor response.Abbreviations nIL-2 natural interleukin-2     

过氧化物酶体增殖物激活受体-γ在炎症性肠病中的表达及意义

目的 观察过氧化物酶体增殖物激活受体-γ(PPAR-γ)在炎症性肠病(IBD)中的表达,探讨其可能的意义.方法 采用免疫组织化学方法检测28例克罗恩病(CD)患者、38例溃疡性结肠炎(UC)患者及30例健康对照肠道组织中PPAR-γ蛋白的表达,并进一步分析PPAR-γ蛋白与IBD临床特征的关系.结果 PPAR-γ在UC患者中表达阳性率为34.21% (13/38),明显低于正常对照63.33%(19/30) 及CD患者60.71%(17/28)(P<0.05);PPAR-γ蛋白表达与UC疾病活动性明显相关(P<0.05),与UC严重程度、病变部位及CD临床特征无明显相关(P>0.05).结论 PPAR-γ蛋白在UC肠道组织中表达降低,且与疾病活动性明显相关.提示PPAR-γ可能在UC发生、发展中发挥重要作用.     

乙型肝炎病毒感染者肝组织IL-12表达及其意义

目的探讨乙型肝炎病毒感染者肝组织白细胞介素12（IL-12）表达与临床表现和肝脏病理学变化的关系。方法应用免疫组化法检测9例正常肝脏组织、183例慢性乙型肝炎（CHB）、41例乙型肝炎肝硬化、37例HBV相关肝癌患者肝组织IL-12表达情况,并与临床特点和病理分级等进行相关性分析。结果 CHB患者肝组织IL-12以弱阳性表达为主,阳性和强阳性表达的比例仅为26.8%,而肝硬化和肝癌患者阳性和强阳性表达的比例分别为36.6%和48.6%,均显著高于CHB患者（P＜0.05）;HBeAg阴转且HBV DNA阴转的CHB患者肝内IL-12阳性表达比例为64.3%,显著高于HBeAg阳性伴肝功能异常者（30.0%）和肝功能正常者（20.4%）（P＜0.05）;未发现IL-12表达与肝脏炎症分级或纤维化分期具有相关性。结论 IL-12可能参与HBV感染后的疾病进展与转归。     

肝纤维化无创诊断研究进展及其临床应用

肝纤维化是各种病因所致慢性肝损伤引起的细胞外基质的过度积聚,最终可能发展成肝硬化.对慢性肝病肝纤维化程度的评估尤为重要,是判断病情、决定是否进行治疗及随访疗效的关键环节.肝脏活体组织检查(肝活检)目前仍被认为是诊断肝纤维化的“金标准”,但由于其有创性,可引起危及生命的并发症,即使可能性很低,仍然限制了它的进一步应用.近年来发展起来的无创性肝纤维化诊断方法逐渐成为国内外学者关注的热点,这些方法完全不同却又相互补充,包括生物学途径,如检测各种肝纤维化的血清学标志物水平;也包括一些物理途径,如通过超声或磁共振弹性成像方法来评价肝组织硬度.这些无创诊断方法首先用于并且确证于慢性丙型肝炎患者,目前正逐渐扩展至其他慢性肝病,如慢性乙型肝炎、非酒精性脂肪性肝病和自身免疫性肝病等,从而降低了肝活检的需求.本文就肝纤维化无创诊断的优缺点和临床应用等方面进行综述.     

Transient elastography to assess liver stiffness in patients with inflammatory bowel disease

BackgroundLiver injury during inflammatory bowel disease (IBD) is primarily diagnosed by liver biopsy, which has a small but serious risk of severe complications. The aim of this study was to assess liver stiffness, and subsequently the prevalence and associations of liver fibrosis in IBD patients with thiopurine therapy and other clinical factors, by using transient elastography (TE).MethodsIn this prospective, international two-center study, included IBD-patients underwent TE measurements. Laboratory results and medication reports, radiology results and historical liver biopsy results were extracted from the patient charts.ResultsTransient elastography results of 168 patients were presented. Moderate and severe fibrosis were detected in 4% (7/168) and 1% (1/168) of the cohort, respectively. Factors contributing to lower liver stiffness were female gender and (historical) exposure to azathioprine. Further, there was a statistical trend towards lower liver stiffness in patients using thiopurines overall (4.7 vs. 5.2 kPa, p = 0.07). Liver stiffness correlated positively with waist circumference, liver enzyme tests, hemoglobin and 6-methylmercaptopurine concentration and negatively with platelet count.ConclusionExposure to thiopurine therapy was not associated with higher liver stiffness, although no clinical difference in severity of fibrosis was detected. Further research should robustly determine the accuracy of TE as an evaluation of liver fibrosis in IBD patients.     

Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis

Summary. The limitations of liver biopsy (invasive procedure, sampling errors, inter‐observer variability and nondynamic fibrosis evaluation) have stimulated the search for noninvasive approaches for the assessment of liver fibrosis in patients with viral hepatitis. A variety of methods including the measurement of liver stiffness, using transient elastography, and serum markers, ranging from routine laboratory tests to more complex algorithms or indices combining the results of panels of markers, have been proposed. Among serum indices, Fibrotest has been the most extensively studied and validated. Transient elastography appears as a promising method but has been mostly validated in chronic hepatitis C with performance equivalent to that of serum markers for the diagnosis of significant fibrosis. The combination of both approaches as first‐line assessment of liver fibrosis could avoid the performance of liver biopsy in the majority of patients with chronic hepatitis C, a strategy that deserves further evaluation in patients with hepatitis B or HIV‐HCV coinfection. Transient elastography also appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. Guidelines are now awaited for the use of noninvasive methods in clinical practice.     

Validation of a procedure to assess ASA-response in patients with decreased,initial TRAP induced aggregation

Whole blood aggregometry on the is a simple, fast and standardized method and it is widely used to assess platelet function under antiplatelet therapy. Reference ranges and a cut-off value as a measure of ASA response were established by measuring arachidonic acid induced aggregation (ASPI-test) in healthy volunteers and cardiac patients after and used to classify patients as ASA responders or non-responders. However, assessing the platelet function is highly affected by pre-analytical and analytical conditions and often reduced aggregation by TRAP induced aggregation (TRAP-test) is seen, rendering the samples difficult for interpretation of the ASPI-test and the responder status to ASA. We hypothesised that in this simplified model any preanalytical factor has the same effect on TRAP-testing as on ASPI-testing and that by calculating the ratio between a defined, normal TRAP-test result and the TRAP-test result measured for the individual patient this ratio could be applied to the measured ASPI-test thereby reaching a more valid discrimination between ASA responders and -non-responders. TRAP- and ASPI-test were performed in blood from ASA-treated volunteers and controls on Multiplate? before an after pneumatic tube delivery as a model to stimulate shear stress induced platelet activation and aggregation. The calculated, normalised ASPI test result after tube delivery did not differ significantly from the initial ASPI test result although tube delivery had a significant impact on the measured ASPI test result. If applied to patients samples a definite judgement on the ASA response status of patients with reduced “general platelet activatability” could be given. Normalisation of the ASPI-test result using the TRAP-test result may provide a method to judge on the ASA response status in patients with decreased initial “general platelet activatability”.     

Noninvasive methods to assess liver disease in patients with hepatitis B or C

The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.     

扶正利湿解毒法体内外逆转肝纤维化

目的:观察扶正利湿解毒法基本方(简称基本方)对肝纤维化的逆转作用.方法:采用DMN诱导大鼠肝纤维化,造模结束后随机分为模型对照组,秋水仙碱组,基本方高剂量组,基本方中剂量组及基本方低剂量组并分组给药,同时设空白对照组.灌胃3wk后检测肝组织Hyp,ALT水平;HE,Masson染色.采用HSC-T6细胞培养,药物作用24h后光镜下观察拍照,检测药物对细胞的抑制率并在电镜下观察药物浓度为2g/L时细胞的变化.结果:基本方高、中剂量均可使大鼠肝组织Hyp,血清ALT显著下降(Hyp:213.73±58.05μg/g,245.95±67.70μg/g vs 317.37±42.06μg/g,P<0.01,P<0.05;ALT:33.56±8.16 kU/L,42.38±14.99 kU/L vs 58±10.32 kU/L,P<0.01,P<0.05);Masson染色肝纤维化分级评分显示,基本方高,中剂量均可使肝纤维化程度显著降低(2.33±0.87,2.63±0.74 vs 3.70±0.67,P<0.01,P<0.01),同时显著改善肝组织炎症、出血及纤维沉积;光镜观察及抑制率检测显示基本方呈剂量依赖性抑制HSC-T6细胞增值.电镜显示基本方主要导致HSC-T6细胞凋亡.结论:基本方显示了显著的体内外逆转肝纤维化作用.